It is known from U.S. Pat. No. 4,767,859 a process for the preparation of aminopterin from folic acid by the direct amination of the pteridine ring of folic acid. Generally, the process is a method for the preparation of aminopterin which comprises reacting folic acid with a silazane in an organic solvent at a temperature from 60 to 180° C., the said solvent being a tertiary amine organic solvent, or, if a catalyst which is acid in nature is present, a basic organic solvent or acetonitrile, and in the absence of ammonia.
In one embodiment, the method describes the use of anhydrous pyridine in a 17 hour reaction at 100° C. to obtain 79% pure aminopterin. In another embodiment, the method describes the use of anhydrous pyridine in a 48 hour reaction at 100° C. to obtain 33.3% pure aminopterin. This level of purity is inadequate for the commercial production of pharmaceutical grade aminopterin.